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Abstract:

An active agent delivery composition is provided that allows topical
delivery of active agents including vitamin A and its derivatives. A
volatile vehicle serves as a coupler for an active agent and an
organosiloxane carrier so as to allow full solubilization of active
agents not normally miscible in silicones and providing a non-irritating,
targeted evaporating composition.

Claims:

1. An active agent topical delivery composition comprising: a volatile
organosiloxane carrier; an active agent selected from the group
consisting of vitamin A or vitamin A derivatives, hydroxy acids, benzoyl
peroxide, and combinations thereof; and a volatile vehicle, said
composition having less than 15% organic hydrocarbon solvent of 6 carbon
atoms or fewer.

2. The composition of claim 1 having an evaporation rate in air of 10 to
200 mg/cm2/minute at 25.degree. C. and atmospheric pressure of 760
mmHg.

3. The composition of claim 1 with an irritancy value of 2 or less.

4. The composition of claim 1 that is a clear solution of said active
agent.

5. The composition of claim 1 wherein said composition has less than 5%
organic hydrocarbon solvent of 6 carbon atoms or fewer.

6. The composition of claim 1 wherein said agent is vitamin A or its
derivatives wherein said vitamin A or its derivatives are present at
between 0.001 to 2 weight percent.

7. The composition of claim 1 wherein said active agent is a vitamin A
derivative selected from the group consisting of: retinal; retinoic acid;
retinyl ester; retinol; tretinoin, isotretinoin, or esters thereof; an
ester or amide of 13-trans retinoic acid; adapalene; tazarotene; or
combinations thereof.

14. The composition of claim 1 wherein said vehicle comprises a volatile
high molecular weight hydrocarbon with 6 to 16 carbon atoms.

15. The composition of claim 14 wherein said vehicle further comprises an
organic solvent of 5 carbons or fewer, or disiloxane.

16. The composition of claim 1 wherein said vehicle is present at from 5
percent to 40 percent by weight.

17. The composition of claim 1 wherein said vehicle is present from 10 to
25 percent by weight.

18. A process of treating a skin condition in a subject comprising:
administering to a subject the composition of claim 1.

19. The process of claim 18 wherein said composition contains less than
5% organic hydrocarbon solvent of 6 carbon atoms or fewer.

20. The process of claim 18 wherein said active agent is vitamin A or its
derivatives present at between 0.001 to 2 weight percent.

21. The process of claim 18 wherein said volatile organosiloxane carrier
is a linear aliphatic polyorganosiloxane.

22. An active agent topical delivery composition consisting essentially
of: an active agent selected from the group consisting of vitamin A or
vitamin A derivatives, hydroxy acids, benzoyl peroxide, and combinations
thereof; a volatile organosiloxane containing carrier present as a
predominant; and a volatile vehicle, said volatile vehicle present at
from 5 percent to 40 percent by weight; the composition having less than
15% organic hydrocarbon solvent of 6 carbon atoms or fewer.

23. The composition of claim 22 wherein said organic hydrocarbon solvent
is ethoxydiglycol.

24. The composition of claim 22 wherein said volatile vehicle is selected
from the group consisting of perfluorohexane, perfluorodecalin,
methoxynonafluorobutane, pentafluoropropane, disiloxane, a linear or
branched C12-C16 alkane, a linear or branched C12-C16 alkane in
combination with an organic hydrocarbon solvent of 5 carbons or fewer and
at a concentration of less than 5% per weight, and combinations thereof.

25. The composition of claim 22 wherein said active agent is selected
from the group consisting of: a retinal; retinoic acid; retinyl ester;
retinol; tretinoin, isotretinoin, or esters thereof; an ester or amide of
13-trans retinoic acid; adapalene; tazarotene; and combinations thereof.

26. A process of solubilizing a derivative of vitamin A in a volatile
organosiloxane carrier in the absence of 15% or greater organic
hydrocarbon solvent of 5 carbon atoms or fewer comprising: combining a
vitamin A derivative with a volatile organosiloxane carrier and a
volatile vehicle.

27. The process of claim 26 wherein said volatile organosiloxane carrier
is present at 50% or greater.

28. The process of claim 26 wherein said step of combining includes said
volatile vehicle at 5-40 percent by weight.

29. The process of claim 26 wherein said volatile vehicle is selected
from the group consisting of perfluorohexane, perfluorodecalin,
methoxynonafluorobutane, pentafluoropropane, disiloxane, isododecane,
isododecane in combination with an organic hydrocarbon solvent of 5
carbons or fewer and at a concentration of less than 5% per weight, a
linear or branched C12-C16 alkane other than isododecane, and
combinations thereof.

Description:

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application depends from and claims priority to U.S.
Provisional Application No. 61/717,830 filed Oct. 24, 2012, and this
application is a continuation-in-part of U.S. application. Ser. No.
13/685,244 filed Nov. 26, 2012, which is a continuation of U.S.
application Ser. No. 12/711,381 filed Feb. 24, 2010, which claims
priority to U.S. Provisional Application No. 61/286,668 filed Dec. 15,
2009, the entire contents of each of which are incorporated herein by
reference.

FIELD OF THE INVENTION

[0002] The invention relates to compositions for topical delivery of
active agents. The compositions relate to delivery of active agents to
the skin with reduced toxicity such as drying, irritation, or
inflammation. The inventive composition is related to delivery of topical
agents such as retinoids to the skin.

BACKGROUND OF THE INVENTION

[0003] The comfort associated with application of topical agents is
related in part to the rate of evaporation of the applied composition on
the skin. A product with a slow evaporation rate could feel greasy on the
skin whereas a product with an overly rapid evaporation rate feels either
as if it has not been applied to the skin at all or leaves the user with
the impression that not enough has been applied possibly leading to
overuse. Combining topical agents with volatile silicones has been found
to provide a pleasing application. Silicones and other organosiloxanes,
however, by themselves are poor solvents for hydrophobic organic active
agents.

[0004] To address the poor solubility in silicones, delivery systems for
these agents commonly require 35% or more organic solvent as a carrier to
solubilize the active agent as well as provide suitability for
combination with volatile compounds that provide pleasing application by
the user. Prior formulations prefer alcohols such as ethyl alcohol as an
organic solvent to solubilize the active agent in a silicone.

[0005] Lipophilic skin care active agents such as retinoids are generally
applied topically to reduce the appearance of aging, for other cosmetic
purposes, or to treat a skin condition such as acne. The retinoids,
however, along with many other active agents contribute to thinning or
drying of the skin. This problem is worsened by including significant
levels of organic solvents that themselves can alter epidermal barrier
lipids and contribute to skin irritation. Ethyl alcohol, as used in the
retinoid composition of U.S. Pat. No. 4,826,828 was believed to be the
solution for topical delivery of hydrophobic agents. Ethyl alcohol, to
the contrary, contributes to skin irritation and dryness. Thus, combining
ethyl alcohol with potentially irritating active agents increases skin
dryness leading to non-optimal use.

[0006] Thus, there exists a need for a hydrophobic active agent delivery
system that provides pleasing application and does not contribute to
toxicity.

SUMMARY OF THE INVENTION

[0007] The following summary of the invention is provided to facilitate an
understanding of some of the innovative features unique to the present
invention and is not intended to be a full description. A full
appreciation of the various aspects of the invention can be gained by
taking the entire specification, claims, drawings, and abstract as a
whole.

[0008] An active agent delivery composition is provided that creates
pleasing administration of an active agent to the skin of a subject
without a greasy feeling residue, includes only non-irritating solution
components at their concentrations, and is a clear solution alone, an
optionally in the presence of one or more additives. The achievement of
these three characteristics of an active agent delivery composition is
provided by the function of a non-irritating volatile vehicle that will
promote solubilization of the active agent in an organosiloxanes carrier
as a primary solvent. In many embodiments, the ability of the volatile
vehicle to produce a clear, fully solubilized solution is surprising in
that in many embodiments the active agent is not fully soluble in either
the organosiloxane carrier or the vehicle alone at the concentrations
used in the composition.

[0010] The inventive composition provides pleasing skin administration
through the use of an organosiloxane carrier that is optionally a linear
aliphatic polyorganosiloxane, optionally ethyl trisiloxane, combined with
an volatile vehicle with a complimentary volatility relative to the
carrier such that the overall composition may have an evaporation rate in
air of 10 to 500 mg/cm2/minute at 25° C. and atmospheric
pressure of 760 mmHg.

[0011] A volatile vehicle is present in the inventive composition to
solubilize the active agent with the carrier while reducing or
eliminating the need for an organic hydrocarbon solvent such as ethanol.
A vehicle is optionally a linear, branched, and/or ring formed perfluoro
C1-C20 alkyl. In some embodiments, a vehicle is a perfluoro
C4-C8 alkyl, optionally a perfluoro C6 alkyl such as
perfluorohexane. A vehicle is optionally a perfluoro ether, optionally,
methoxynonafluorobutane or ethoxynonafluorobutane. A vehicle is
optionally perfluorohexane, perfluorodecalin, methoxynonafluorobutane,
pentafluoropropane, disiloxane, isododecane, isododecane in combination
with an organic hydrocarbon solvent of 6 carbons or fewer and at a
concentration of less than 15% per weight, a linear or branched
C12-C16 alkane other than isododecane, or any combination
thereof. The vehicle is optionally present from about 15 to 25 percent by
weight.

[0012] An optional organic hydrocarbon solvent of 6 carbon atoms or fewer
is optionally included or is absent. Optionally, the organic hydrocarbon
solvent is present at less than 15 percent by weight. Optionally, the
organic hydrocarbon solvent is present at less than 5 percent by weight.
The composition satisfies the long felt need for a system of active agent
delivery that does not require an alcohol solvent at concentrations in
excess of 15%, which in the prior understanding was more typically of 30%
or greater, to solubilize the active agent in an organosiloxane carrier.
Thus, the resulting compositions do not suffer the skin irritancy
produced by such concentrations of organic hydrocarbon solvent, and helps
reduce any irritancy that is may be a characteristic of the active agent
itself.

[0013] Also provided are processes of treating a skin condition in a
subject. The skin condition may be, for example, acne, wrinkles, dryness,
cancer, or perspiration. The inventive process includes applying an
inventive composition to the skin of a subject

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

[0014] The following description of particular embodiment(s) is merely
exemplary in nature and is in no way intended to limit the scope of the
invention, its application, or uses, which may, of course, vary. The
invention is described with relation to the non-limiting definitions and
terminology included herein. These definitions and terminology are not
designed to function as a limitation on the scope or practice of the
invention but are presented for illustrative and descriptive purposes
only. While the processes or compositions are described as an order of
individual steps or using specific materials, it is appreciated that
steps or materials may be interchangeable such that the description of
the invention may include multiple parts or steps arranged in many ways
as is readily appreciated by one of skill in the art. It is to be
understood that the present invention is not limited to particular
embodiments described, which may, of course, vary.

[0015] The invention has utility for topical delivery of active agents.
The invention has more specific utility for the delivery of hydrophobic
active agents to the skin with reduced agent or solvent related side
effects and improved comfort and user compliance. Some embodiments have
utility for the treatment of one or more conditions of the skin. Also
provided are embodiments that have utility for fully solubilizing a
hydrophobic active agent in a silicone providing a clear solution with
15% or less of organic hydrocarbon having 6 carbons or fewer.

[0016] The inventive composition includes an active agent combined with an
organosiloxane carrier and a compatible volatile vehicle.

[0017] As used herein the term "active agent" refers to a molecule
suitable for delivery to the skin or mucosal regions of a subject.
Optionally, an active agent has pharmaceutical activity and is present
for the treatment or prevention of a skin condition. Active agents are
optionally low polarity molecules such as those having a hydrocarbon
chain of three or more carbons, but may also include materials of higher
polarity. Examples of active agents illustratively include: vitamin A or
its derivatives; hydroxy acids; aromatic molecules such as benzoyl
peroxide and resorcinol; azelaic acid; antimicrobials such as azelaic
acid, erythromycin, sodium sulfacetamide, tetracycline and derivatives,
and clindamycin; anti-neoplastic agents and/or ophthalmic agents
illustratively including 5-fluorouracil, doxorubicin, imiquimod, and
sodium[o-(2,6-dichloranilino)phenyl]acetate; anti-viral agents
illustratively ganciclovir, trifluorothymidine and related compounds;
steroidal and nonsteroidal anti-inflammatory agents illustratively
flurbiprofen, ibuprofen, naproxen, indomethacin and related compounds;
anti-mitotic drugs illustratively colchicine taxol and related compounds;
drugs that act on actin polymerization illustratively phalloidin,
cytochlasin B and related compounds; inhibitors of dihydropyrimidine
dehydrogenase (DPD), thymidine phosphorylase (TP) and/or uridine
phosphorylase (UP) enzyme inhibitors; ultraviolet light (UV) filters
illustratively benzophenone derivatives such as oxybenzone, octocrylene,
octyl methoxycinnamate, and avobenzone; radiation proactive agents
illustratively methyluracils such as 6-methyluracil and 4-methyluracil;
and immunomodulating molecules such as tacrolimus, and pimecrolimus. An
active agent need not have pharmaceutical activity. Other active agents
are illustratively cosmetics such as pigments, dyes, and fillers. It is
appreciated that an inventive composition optionally includes more than
one active agent. Optionally, 2, 3, 4, 5, 6, or more active agents are
present in an inventive composition. An active agent is optionally a
prodrug that is converted to a desired active species optionally in the
skin or layer thereof.

[0018] An active agent is optionally a lipid such as those suitable for
controlling perspiration. Lipids optionally have an HLB of less than
about 12, less than about 8, or optionally less than about 6.
Illustrative examples of lipids include glyceryl monostearate, glyceryl
monoisostearate, glyceryl monomyristate, glyceryl monoleate, diglyceryl
monoisostearate, propylene of glycol monostearate, propylene glycol
monoisostearate, propylene glycol monocaprylate, sorbitan
monoisostearate, sorbitan monocaprylate, sorbitan monoisooleate, glyceryl
monolaurate, glyceryl monocaprylate, glyceryl monocaprate, mixtures
thereof or the like. Optionally, the lipid is glyceryl monolaurate, made
available by suppliers like Fitz Chem Corporation under the name MONOMULS
90-L12.

[0019] Typically, the lipid, when present, makes up from about 4% to about
35%, and optionally, from about 5% to about 20%, and optionally, from
about 10% to about 15% by weight of the composition, based on total
weight of the composition and including all ranges subsumed therein.

[0020] An active agent is optionally vitamin A or a derivative of vitamin
A. Examples of vitamin A or its derivatives illustratively include
retinoids such as retinal, retinoic acid, retinyl ester, retinol,
tretinoin or esters or amides thereof; isotretinoin or esters or amides
thereof; adapalene, tazarotene, C9- or C13-cis retinoids or their
derivatives (e.g. esters or amides), C13 trans retinoids or their
derivatives (e.g. esters or amides), and the like. Specific examples of
retinoids include those described in U.S. Pat. Nos. 5,837,728, 4,677,120
and 4,885,311. One specific example of a derivative of vitamin A is
hydroxypinacolone retinoate.

[0021] Examples of hydroxy acids illustratively include beta hydroxy acids
such as salicylic acid, acetylsalicylic acid, and the like may be
substituted for or combined with the retinoid.

[0022] While the description uses retinoids as illustrative examples of an
active agent, the specification is not limited as such. Other active
agents are similarly operable herein. It is appreciated that other active
agents are similarly substitutable with the retinoid, for example benzyol
peroxide, or other active agent.

[0023] The compositions of the invention may include 0.005 to 1.0 weight
percent retinoid, in which case they are optionally applied directly to
the skin, or supplied as a more concentrated solution containing higher
levels of active agent, in which case prior to application they are
diluted optionally by means of a cosmetically acceptable carrier to a
desired level such as 0.005 to 1.0 weight percent for retinoid. In the
formulations of the invention, water is optionally minimized or
eliminated to improve the stability of retinoid and to minimize the
potential for separation of the oil and water. Optionally, water is
present at less than 2%. One of ordinary skill in the art will recognize
that differing levels of active agent will be operable herein depending
on the desired final amount of active agent to be administered.

[0024] Optionally, active agent is present in less than 30 percent w/w
amounts. Optionally, active agent is present at a weight percent of 30,
29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12,
11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.01, 0.001, 0.0001, or any
level or range therebetween. Optionally, active agent is present at 20
percent w/w. Illustratively, when azelaic acid is an active agent it is
present at 15 to 25 percent w/w. A vitamin A derivative is optionally
present at 0.001 to 2 percent by weight. Imiquimod is optionally present
at 3 to 8 percent by weight. Benzoyl peroxide is optionally present at 1
to 10 percent by weight. It is within the skill of the art to determine
the optimal level of active agent in either a concentrated solution or a
final solution for application.

[0025] An active agent is provided in a carrier. A carrier is optionally
present from 10 to 75 percent w/v. In typical embodiments, a carrier is
present as a predominant component in a composition. Optionally, a
carrier is present at 50% or greater w/v. Carriers are optionally
volatile compounds such as volatile silicones. The use of a volatile
carrier allows application of the active agent to the skin and is capable
of evaporating so as to leave a pleasing feel to the user. Among the many
possible carriers, the siloxanes offer excellent evaporation properties
and are preferred. Siloxanes are illustratively cyclic organosiloxanes or
non-cyclic organosiloxanes. Examples of cyclic organosiloxanes
illustratively include cyclic polydiorganosiloxanes,
cyclotetradimethicones and cyclopentadimethicones. Linear
organopolysiloxanes are illustratively alkyl-, alkoxy- or
phenyldimethicones, and alkyl-, alkoxy- or phenyltrimethicones.
Optionally, a carrier is an aliphatic volatile organosiloxane. Aliphatic
volatile organosiloxanes optionally have from two to six silicon atoms.
Optionally, an aliphatic volatile organosiloxane is a linear
polyorganosiloxane such as a polyorganosiloxane with 2 to 6 silicon
atoms, optionally, an organo-trisiloxane, disiloxane, or combinations
thereof. Disiloxane itself has a very rapid evaporation profile on the
skin. As such, it is optionally not used a as a carrier. Optionally, a
carrier is ethyl trisiloxane. It is appreciated that an inventive
composition optionally includes more than one carrier.

[0026] Suitable organosiloxane carriers preferably are a fluid that can
evaporate on contact with the skin in less than one hour in a surrounding
air environment at room temperature (25° C.) and standard
atmospheric pressure (760 mmHg). An organosiloxane carrier is liquid at
room temperature. An organosiloxane carrier optionally has an evaporation
rate ranging from 10 to 500 mg/cm2/minute, at 25° C. and
atmospheric pressure of 760 mmHg. In some embodiments, the organosiloxane
carriers used in the invention have an evaporation rate ranging from 20
to 200 mg/cm2/minute at 25° C. and atmospheric pressure of
760 mmHg. In some embodiments, the organosiloxane carriers used in the
invention have an evaporation rate ranging from 100 to 200 mg/sq
cm/minute at 25° C. and atmospheric pressure of 760 mmHg.

[0027] Volatile organosiloxanes optionally are lightweight carriers that
evaporate on application and thus have an elegant, light-weight "feel" on
the skin. Volatile organosiloxanes, however, are typically limited in
their ability to dissolve low polarity (i.e. usually greater than C7-C8))
organic compounds like retinoids. For example, when relatively low
therapeutic levels of retinol (0.1-0.2% w/v) are dissolved in
cyclomethicone alone, hazy solutions result due to incomplete
solubilization in the organosiloxane. To address this issue vehicles were
sought that would be both capable of creating clear solutions of active
agent in a volatile organosiloxane carrier, but also have an appropriate
evaporation rate in combination with the volatile organosiloxane when
placed on the skin so as maintain the light-weight feel on the skin
experienced by a user. A vehicle must also not promote unacceptable skin
irritation when used at the concentration necessary in the composition.

[0028] Traditional methods of solubilizing active agents in a volatile
organosiloxane used volatile low molecular weight hydrocarbons as an
organic solvent, such as ethanol. This required high hydrocarbon
concentrations typically of 30% or greater. While these organic solvents
did promote solubilization of active agents in the silicone carriers,
they also promote undue skin dryness and irritation. When combined with a
potentially irritating active agent such as benzyol peroxide, retinoids,
or others, this results in a negative experience for the user. Thus, a
vehicle must also not promote skin irritation when used at the final
concentration in the material.

[0029] Among the nearly infinite possibilities of vehicles to select from
when searching for a material that could function with both an active
agent and a volatile organosiloxane, it was unexpectedly discovered that
an organic polyhalogenic vehicle alone or in combination with less than
5% low molecular weight hydrocarbon organic solvent (6 carbons or fewer),
or particular volatile hydrocarbons in combination with less than 5% low
molecular weight hydrocarbon organic solvent (6 carbons or fewer) could
incorporate an active agent such as a retinoid at appropriate therapeutic
levels and reduce the levels of low molecular weight hydrocarbon solvent
to less than 5 percent in contrast to U.S. Pat. No. 4,826,828, which
required 35-60 percent w/w hydrocarbon solvent. It was particularly
surprising that such a combination will work to solubilize an active
agent as the organic polyhalogenic materials, the volatile hydrocarbons,
and the carriers are unable to fully solubilize the active agent at the
therapeutic concentration alone, particularly at low temperature such as
4° C. at which the active agent will crystallize and fall out of
solution in either of the carrier or other vehicle materials alone. Thus,
there is no expectation that the combination of the two material types,
each of which do not allow full, stable, solub lization of the active
agent, will do so when the materials are combined.

[0030] The discovery of using organic polyhalogenic vehicles to promote
solubility in organosiloxane carriers is unexpected due to the fact that
organic polyhalogenic vehicles are poor solubilizers of molecules such as
retinoid on their own. Combined with the knowledge that organosiloxanes
are poor solvents, one of ordinary skill in the art has no expectation of
success combining two poor solubilizers to form a system that effectively
and fully solubilizes active agents. Organic polyhalogenic solvents are
optionally those disclosed in U.S. Pat. No. 6,251,375. In particular
instances, vehicles incorporate a halogen such as one or more fluorine
atoms. A vehicle is optionally a substituent containing C1-C20
alkyl, alkenyl, or alkynl, any of which is cyclic, bicyclic, linear,
branched, or combinations thereof, wherein a substitutent is a fluorine
atom. A vehicle is optionally a fluorine substituent containing molecule
that is an aryl, a C1-C20 alkyl, a C2-C20 alkenyl, or
a C2-C20 alkynyl, wherein the molecule optionally includes a
second substituent that is N, O, or S. In some embodiments, a vehicle is
a perfluoro C4-C12 alkyl, optionally a perfluoro C6 alkyl
such as perfluorohexane available from F2 Chemicals Ltd. (Lancashire,
UK). In some embodiments, a vehicle is a bicyclic perfluoro molecule such
as perfluorodecalin available from F2 Chemicals Ltd. In some embodiments,
the use of perfluorodecalin produces a final composition with too low an
evaporation rate resulting in a greasy feeling on the skin. As such,
perfluorodecalin is optionally excluded. In some specific instances, a
vehicle is a perfluoro ether. In some particular instances, a vehicle is
methoxynonafluorobutane or ethoxynonafluorobutane available from 3M
Specialty Materials, St. Paul, Minn. Other illustrative examples of
pefluoro vehicles include: perfluorodimethylcyclohexane available from F2
Chemicals Ltd.; perfluoromethyldecalin available from F2 Chemicals Ltd.;
perfluoropentane available from Fluoromed, Round Rock, Tex.); or
perfluoroperhydrophenanthrene available from F2 Chemicals Ltd.
Optionally, a combination of one or more polyhalogenic compounds are used
to form a vehicle. Illustratively, a vehicle may be a blend of two or
more of perfluorohexane, perfluorodecalin, pentafluoropropane,
perfluorodimethylcyclohexane, or perfluoroperhydrophenanthrene.
Optionally, a vehicle is a blend of perfluorohexane, perfluorodecalin,
and pentafluoropropane, sold as Fiflow BB61 sold by the Innovation
Company, France.

[0031] In some embodiments, a vehicle includes a particular volatile
silicon containing material alone or in combination with a volatile low
molecular weight hydrocarbon. Illustrative volatile silicon containing
materials useful as a vehicle include disiloxanes (optionally disiloxane
at 0.65-5 cSt), among others. In some embodiments, a vehicle is not ethyl
trisiloxane. Optionally, a vehicle is disiloxane at 5-15% by weight in
combination with a volatile low molecular weight hydrocarbon present at
5% or less by weight such as ethanol. It was discovered that the presence
of disiloxane will promote the appropriate evaporation profile and can
reduce the amount of organic solvent (e.g. ethanol) to less than 5% by
weight necessary to produce fully solubilized active agent, thus
promoting the pleasing feel on the skin and creating complete
solubilization (i.e. clear solution) of the active agent in the carrier.
This represents a delicate balance of materials such that the volatile
components (e.g. 0.25-1 ml) will evaporate from the skin preferably in
20-60 seconds, optionally 20-30 seconds while simultaneously keeping the
level of organic solvent at a level that will not irritate the skin.

[0032] In some embodiments, a vehicle includes a volatile high molecular
weight hydrocarbon such as linear or branched volatile hydrocarbons with
6 to 16 carbon atoms, alone, combined with a second or additional vehicle
with a lower boiling point, or combined with less than 5% of organic
solvent of 5 carbons or fewer. The usefulness of this vehicle type was
also unexpected due to the inability of such a vehicle to solubilize the
active agent at low temperatures such as 4° C. for a sufficient
period of time (i.e. 30 days). A volatile high molecular weight
hydrocarbon vehicle is linear or branched and illustratively includes
C8-C16 alkanes, branched C8-C16 esters, and mixtures
thereof. Optionally, a volatile high molecular weight hydrocarbon vehicle
is linear or branched and illustratively includes C10-C16
alkanes, branched C10-C16 esters, and mixtures thereof.
Illustrative examples of a volatile high molecular weight hydrocarbon
vehicle include isododecane, methylpentadecene, and isohexadecane.
Specific examples of a volatile high molecular weight hydrocarbon vehicle
include: isododecane sold as Permethyl 99A from Presperse (Somerset,
N.J.); a combination of isododecane, hydrogenated
tetradecenyl/methylpentadecene sold as SMART-5 from IMCD, The
Netherlands; isohexadecane sold as Permethyl 101A from Presperse; the
combination of C13-16 isoparaffin, C12-14 isoparaffin, and C13-15 alkane
sold as SiClone SR-5 from Presperse; the combination of coconut alkanes
and coco-caprylate/caprate sold as Vegelight 1214LC by Grant Industries
(Elmwood Park, N.J.); coconut alkanes available from Biosynthis; and
PPG-3 Benzyl ether ethylhexanoate sold as Crodamol SFX by Croda (Edison,
N.J.).

[0033] In some embodiments a volatile high molecular weight hydrocarbon is
used in conjunction with a second vehicle with a lower boiling point. A
volatile high molecular weight hydrocarbon alone is typically not
sufficiently volatile alone and leaves an oily feel on the skin due to
this relatively low evaporation rate. Supplementing the volatile high
molecular weight hydrocarbon with a second vehicle of lower boiling point
will promote the pleasing feel in the skin by creating a desired overall
compositional evaporation profile. A second vehicle is optionally an
organic polyhalogenic vehicle or disiloxane. Disiloxane when used as a
second vehicle is optionally of low viscosity such as 0.5 to 1.2 cSt. A
second vehicle is optionally present at an amount that is 30% or less by
weight, optionally 25% or less by weight.

[0034] In some embodiments, a volatile high molecular weight hydrocarbon
is used in conjunction with an organic solvent of 5 carbons or fewer used
at an overall amount of less than 5% by weight. An organic solvent used
as such low levels was previously thought to be unable to promote
solubility in a silicone based carrier of an active agent such as a
vitamin A derivative (e.g. retinoid). This explains why the art
recognized knowledge preferred higher levels of organic solvents such as
ethanol. The high levels of ethanol (i.e. more than 15%, or to a lesser
degree 5% or more) promotes skin irritation. It was unexpectedly
discovered that a volatile high molecular weight hydrocarbon vehicle
could be combined with the low level of organic solvent of 5 carbons or
fewer to have multiple beneficial effects. The combination will fully
solubilize otherwise not fully soluble active agents such as retinoids in
organosiloxane carriers, will provide the appropriate overall evaporation
profile of the overall material, and will protect against skin
irritation. In some embodiments, an organic solvent of 6 carbons or fewer
is ethanol, or isopropyl alcohol. An organic solvent of 5 carbons or
fewer when used in conjunction with a volatile high molecular weight
hydrocarbon vehicle is used at 5% or fewer by weight, optionally less
than 5% by weight, optionally between 2-3 percent by weight. The organic
solvent is preferably anhydrous.

[0035] A vehicle optionally has a boiling point less than 78° C.
Optionally, a vehicle has a boiling point below 65° C. A vehicle
is optionally present at a final concentration of about 2 percent to 40
percent w/w. Optionally, a vehicle is present at from 15 percent to 25
percent w/w. Optionally, a vehicle is present at 20% w/w. Optionally, a
vehicle is present at from 1-5% w/w, optionally less than 5% w/w. It is
appreciated that more than one vehicle is optionally present in an
inventive composition. Optionally, 2, 3, 4, 5, 6, or more vehicles are
present in an inventive composition. In some embodiments, a vehicle is
not a perfluoroether.

[0036] The inventive composition is optionally formulated with levels of
organic solvent. An organic solvent is optionally volatile at ambient
temperatures and pressures. Optionally, less than 35% organic solvent is
included. Optionally, less than 30% organic solvent is included.
Optionally, the level of volatile organic solvent is less than 15 percent
w/w. Optionally, an organic solvent is present at 5% or less w/w,
optionally an organic solvent is present at less than 5% by weight.
Optionally, an organic solvent is absent. An organic solvent is
optionally an alcohol of 6 carbons or fewer. Optionally, an alcohol is an
ethoxydiglycol, ethanol, or isopropyl alcohol. Optionally, an organic
solvent is ethoxydiglycol present at 10 percent w/w or less. Optionally,
ethoxydiglycol is present at 3 percent w/w. Organic solvent is optionally
ethanol at less than 15% by weight, optionally less than 10% by weight,
optionally 5% or less by weight, optionally less than 5% by weight. The
level of organic solvent optionally does not induce noticeable drying or
other toxic effects on the skin as opposed to systems that require
volatile organic solvents such as ethanol at much higher concentrations.
It is appreciated that more than one organic solvent is optionally
present in an inventive composition. It is further appreciated that the
inventive composition may be entirely free of organic hydrocarbon solvent
of 6 or fewer carbons, optionally 5 or fewer carbons.

[0037] It is a particularly unexpected and surprising discovery of the
subject invention that stable, fully solubilized solutions of active
compounds in the carrier can be prepared with less than 15 percent w/w
organic solvent when combined with a vehicle at 5 percent to 40 percent
w/w. It is particularly surprising that a vehicle at 5 percent to 40
percent w/w can promote a stable fully solubilized solution with less
than 5% organic hydrocabon solvent. The findings are particularly
surprising when such an active agent is not fully soluble in either the
carrier or the vehicle. It was unexpected that an active agent that is
not fully soluble at a desired concentration in a volatile organosiloxane
carrier and not fully soluble in a organic polyhalogenic vehicle, for
example, would be fully soluble in a combination of volatile silicone
carrier and organic polyhalogenic vehicle at that concentration,
particularly when less than 5% of organic hydrocarbon solvent such as an
alcohol (e.g. ethanol) is present, or such an organic solvent is absent.
A composition is optionally free of other components to promote
solubility of an active agent other than the volatile organosiloxane
carrier and volatile vehicle. In some embodiments, the composition is
free of other components to promote solubility of an active agent other
than a volatile organosiloxane carrier that is a linear
organopolysiloxane (optionally ethyl trisiloxane) and a volatile vehicle
that is optionally perfluorohexane, pentafluoropropane, perfluorohexane,
perfluorodecalin, methoxynonafluorobutane, disiloxane, a volatile high
molecular weight hydrocarbon such as isododecane, ethanol or isopropyl
alcohol at less than 15% by weight, PPG-3 Benzyl ether ethylhexanoate, or
a combination thereof.

[0038] In many embodiments, the composition is substantially free of
water, where the term substantially free of water is as low as
practicably achievable in standard manufacturing conditions. The absence
of water helps promote a uniform clear composition that is not subject to
separation of oil and water phases and is not a suspension. Also, the
absence of water will stabilize hydrophobic active agents in the
compositions.

[0039] The composition is tailored to provide a clear solution of active
agent that has a desirable overall evaporation profile and does not
promote unacceptable skin irritation. The composition, therefore includes
a volatile organosiloxane carrier that when combined with the volatile
vehicle creates a clear solution in the absence of water. The composition
has an evaporation rate of 0.01 to 15 mg/cm2/minute on contact with
the skin or other surface at 30-32° C. in an air atmosphere at
room temperature (25° C.) and standard atmospheric pressure (760
mmHg), and which is liquid at room temperature. Optionally, the
composition has an evaporation rate ranging from 5-500 mg/cm2/minute
at 25° C. and atmospheric pressure of 760 mmHg. In some
embodiments, the composition has an evaporation rate ranging from 10 to
200 mg/cm2/minute at 25° C. and atmospheric pressure of 760
mmHg. Optionally, evaporation of 0.3-0.6 ml the volatile components when
placed on the skin will be complete in 15-60 seconds, optionally 20-40
seconds, optionally 20-30 seconds. Such an evaporation profile of the
composition will create the pleasing feel on the skin. Longer evaporation
times produce an "oily" feel to the skin, whereas more rapid evaporation
times leave the subject feeling as if nothing was applied to the skin
possibly leading to overuse.

[0040] In addition, the composition does not promote unacceptable
irritation of the skin. Skin irritation can be tested using a chromameter
to measure skin redness produced by a test composition relative to that
of a control or prior to application. An irritancy value in this standard
art recognized test of 2.5 or less using a Minolta Chroma Meter is
considered acceptable, but it is preferred that a composition have an
irritancy value of less than 2, preferably less than 1.5, more
preferably, 1.3 or less.

[0041] A composition of active agent, organosiloxane carrier, and volatile
vehicle is a clear liquid representing complete or visually complete
solubilization of the active agent in the volatile organosiloxane carrier
in the presence of the vehicle. The presence of other additives may be
used to alter the level of clarity, but optionally do not alter the
solubilization level of the active agent. When a composition is a liquid,
a clear solution is optionally has 90% transmittance at a desired
wavelength relative to the same composition absent the active agent.
Transmittance is optionally 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%,
99.5%, or in excess of 99.5% at a desired wavelength relative to the same
composition absent the active agent. Methods of measuring transmittance
using a spectrophotometer are well known in the art. A non-clear solution
is opaque or possesses a haze or slight haze upon visual inspection.

[0042] Importantly, the compositions are stable in that the combination of
the vehicle with the carrier will maintain the active agent in solution,
and as such are capable of maintaining a clear solution at reduced
temperature for a significant period of time. Illustratively, the
composition will be free of active agent crystallization at a temperature
of -20 to 10° C. for a period of 30 days or more. The compositions
are in some embodiments free of active agent crystallization at a
temperature of 4° C. for 30-90 days.

[0043] The composition optionally includes other additives or
pharmaceutical carriers illustratively including: stabilizers such as the
anti-oxidant BHT; surfactants illustratively Laureth-4; anti-oxidants
illustratively vitamins C and E, and Green tea extract (i.e. Camellia
sinensis) or SILOX GT from Collaborative Labs, Stony Brook, N.Y.; and
emollients illustratively the mixture or single components of the
emollient sold under the brand name SYMREPAIR available from Symrise,
Teterboro, N.J. One of ordinary skill in the art readily appreciates
additives suitable for use with the present invention such as to provide
desired flow characteristics, absorption, evaporation, delivery of active
agent, conversion of a prodrug, or other desired characteristic.

[0045] The compositions of the invention are also optionally diluted to
the appropriate active agent level for application by using other
topically acceptable compounds or vehicles that are optionally miscible
with a retinoid or other active agent of the invention. Other cosmetic
additives are optionally employed either in the compositions of the
invention or in those compositions when diluted with a suitable solvent.

[0046] Also provided are processes of fully solubilizing one or more
retinoids in a solvent that is predominantly an oranosiloxane carrier.
Fully solubilized active agents produce a clear material as defined
herein. A process includes combining an active agent with a carrier at a
concentration in which the active agent is not fully soluble in the
volatile carrier. A process includes combining a volatile vehicle as
defined herein with an active agent and a carrier to create a clear
solution. An active agent is optionally vitamin A, or a vitamin A
derivative such as a retinoid or derivative of a retinoid. Optionally, a
vitamin A derivative is hydroxypinacolone retinoate or other esters or
amides of 9- or 13-cis or trans-retinoids. It is known that vitamin A
derivatives are poorly solubilized in volatile organosiloxane carriers.
The combination of a volatile vehicle as defined herein surprisingly
promotes visually complete solubilization of the vitamin A derivative in
the carrier in the absence of water or greater than 5% organic solvent of
5 carbons or fewer such as ethanol.

[0047] Numerous skin or systemic conditions are treatable with the
compositions illustratively including acne, wrinkles, dryness, eczema,
psoriasis, actinic and nonactinic keratoses, rosaceous, among others.
U.S. Pat. No. 3,932,665 describes retinal as a therapeutic agent in a
method for treating acne by topical application. The topical
administration of 5-fluorouracil for treatment of keratoses is described
in U.S. Pat. No. 4,034,114. The inventive composition reduces the
associated side effects that typically accompany topical or
ophthalmologic administration of active agents while simultaneously
providing a pleasing feel on the skin thereby improving patient
compliance.

[0048] The inventive composition is suitable for topical delivery of an
active agent. The inventive composition illustratively includes an active
agent formulated in a carrier containing volatile organosiloxane and
volatile vehicle. With such a carrier, active agent levels needed to
achieve beneficial effects are minimized and the potential for irritant
effects to the skin by the active agent (e.g. retinoids) are greatly
diminished. Moreover, active agent is stable when formulated in the
organosiloxane carrier compositions of the invention in contrast to other
conventional carriers.

[0049] The compositions formulated as described herein with a retinoid as
an active agent are optionally topically applied to the skin at a
concentration that results in application of 0.005 to 1.0 weight percent
retinoid, optionally 0.01 to 0.50 weight percent retinoid. A composition
is optionally applied in the areas where fine lines, wrinkles, dry or
inelastic skin or large pores are observed. Optionally, a moisturizer is
applied with or after application of the inventive compositions to
enhance the tactile comfort associated with application of the
compositions and to enhance the wrinkle effacement and other benefits
achieved by the compositions. An improved characteristic of the inventive
composition is that the use of additional moisturizers is not required,
but also not precluded.

[0050] Optionally, moisturizing efficacy is achieved in the compositions
of the present invention containing the active agent, thereby precluding
the need for a separate moisturizer. Therefore, optional compositions of
the invention are formulated to include moisturizing components that are
compatible with the volatile organosiloxane carrier to a level of up to
35% by weight of the final formulation. Preferred moisturizing
ingredients are illustratively petrolatum, ethylhexyl palmitate,
cholesterol fatty acid ceramide, and squalane. The addition of one or
more moisturizing components is beneficial when the inventive composition
is applied to previously dried skin or under conditions where dryness
commonly occurs such as in cold climates, or winter months. Optionally, a
moisturizing component is applied where the active agent itself has a
drying effect such as when retinoid or 5-fluorouracil is applied.

[0051] With daily application of a retinoid containing composition, skin
texture, color and tone will improve. Wrinkles and fine lines will be
reduced with minimal irritant effects.

[0052] An inventive composition is optionally applied to the skin of a
subject. A subject is optionally a patient. A subject is optionally a
mammal such as humans, non-human primates, horses, goats, cows, sheep,
pigs, dogs, cats, and rodents.

[0053] An inventive composition is optionally provided as a lotion, cream,
gel, bar, ointment, or in pad form. Optionally, the composition is
provided in a single use container the contents of which are applied
directly to the stratum corneum of a subject or applied to an applicator
pad for subsequent delivery to the subject.

[0054] A cooling effect is optionally observed upon application of the
inventive composition. Cooling effect as used herein means reducing the
temperature of skin, optionally, from about 1° C. to about
2° C. upon application. The cooling effect includes the effect
that results from carrier or vehicle evaporation.

[0055] The inventive composition is optionally administered one to three
times daily. Optionally, the inventive composition is delivered once
daily. Optionally, the inventive composition is administered weekly,
biweekly, monthly, or any subdivision thereof. It is appreciated that the
inventive composition be administered for an amount of time suitable for
efficacy of the active agent. Optionally, the inventive composition is
administered for one to six weeks. Optionally, the inventive composition
is administered indefinitely.

[0056] Also provided is a process of formulating an inventive composition
optionally for pleasing administration to the skin of a subject. An
inventive process illustratively includes making a first solution by
solubilizing one or more active agents optionally in an organic solvent
preferably performed with gentle mixing in low to no light conditions.

[0057] A second solution is made by mixing additives such as emollients
and vitamins. The second solution is added to and mixed with the first
solution. Mixing is preferably in the dark under gentle mixing
conditions.

[0058] A third solution of carrier and vehicle is made and the third
solution is added to the combined first and second solutions to form a
composition. Mixing is optionally non-vortex, gentle mixing in low light
or darkness. Mixing is preferably for 120 minutes. The composition is
preferably stored under inert gas such as nitrogen gas.

[0059] It is appreciated that low to no light conditions are important
should light sensitive components be present in the composition. In the
absence of light sensitive components, the inventive process is
optionally performed in ambient or other lighting conditions.

[0060] The inventive process is optionally performed at ambient
temperature and pressure conditions. Optionally, the inventive process is
performed by heating one or more components or solutions.

[0061] Various aspects of the present invention are illustrated by the
following non-limiting examples. The examples are for illustrative
purposes and are not a limitation on any practice of the present
invention. It will be understood that variations and modifications can be
made without departing from the spirit and scope of the invention. One of
ordinary skill in the art readily knows how to synthesize or commercially
obtain the reagents and components described herein.

[0064] Formula A is transferred to opaque holding containers with nitrogen
head-space for storage. 60 mL of Formula A is then transferred to 2 oz.
amber glass bottles with a purified nitrogen gas head-space and stored
protected from light until used.

Example 2

[0065] A Formula B solution is prepared and stored as in Example 1 with
the exception that Formula B includes perfluorohexane alone or in
combination with perfluorodecalin and pentafluoropropane at 5% by weight
in the place of methoxynonafluorobutane. Formula B also includes 8-12%
disiloxane. An illustrative Formula B solution is illustrated in Table 2.

[0071] Formulas A-G are subjected to characterization for clarity and
propensity to cause skin irritancy. Clarity is observed by visual
observation by a single blinded evaluator and scored on a relative scale
of C=clear, SH=slightly hazy, H=hazy, and O=opaque. Data are presented in
Table 8.

[0072] The compositions of Formulas A-G are also analyzed for propensity
to cause skin irritancy. Eight volunteer subjects in normal health and
that do not exhibit any evidence of acute or chronic disease including
dermatological or ophthalmologic problems are administered one of Formula
A-H. The compositions are applied to both sides of the face in areas that
are devoid of warts, nevi, moles, sunburn, suntan, scars and active
dermal lesions. After an incubation time of 2 hours, measurements are
made using a Minolta Chroma Meter as per the manufacturer's instructions.
The values in the test area of each side of the face are averaged.
Results are presented in Table 8.

[0073] Each of the test formulations of Formulas A-F demonstrate low
irritancy levels whereas the comparator solution (Formula G) that is
typical of prior retinoid compositions produces significant irritation of
the skin.

[0074] With respect to clarity, all of the formulas are clear with the
exception of Formula E which shows a slight haze. This is due to the
benzyl ether ethylhexanoate being less effective as a solvent at these
levels. Increasing the benzyl ether ethylhexanoate level is expected to
clarify the solution.

Example 9

[0075] A solution of Formula H is prepared and stored as in Example 1.
Formula H is as illustrated in Table 9.

[0076] The composition of Formula H is tested for clarity as per Example
8. The blinded tester characterized the formulation as clear. Formula H
also demonstrates low irritancy levels when measured in the skin
irritancy test of Example 8 with an irritancy level of 1.1. This is due
to the low irritancy of the disiloxane and the ethyl trisiloxane, as well
as the very low level of ethanol which is less than in Formula C.

[0078] A split face test is performed by using test Formulas A-F and H or
the comparator of Formulas G or I as follows. Twelve females aged 20 to
59 apply a single test formula to one side of their faces and a
comparator to the other side once daily for eight weeks. Thin shavings of
the skin on each side of the face are taken before the test begins and
after the eight week test period. The skin shavings after the test are in
better condition than those before the test in all twelve women in the
test formula groups. The majority of the women in the comparator groups
show skin improvement, but several do not. The skin of all women is both
thicker and more organized after the test than before. All women in the
test formula groups report improved moisture in the tested skin whereas
the comparator group issues complaints of drying and cracking of the
tested skin areas.

Example 12

[0079] The ability of an electric current to flow through the stratum
corneum provides an indirect measurement of the corneum's water content.
The panelists who participated in the study in Example 11 are assessed
for moisturization using an IBS impedance/conductance meter. At least
twelve hours elapse between the last product application and the skin
conductance measurement. The data demonstrate that the test formula
treated sides are moister (higher conductance readings at all measurement
time points) than comparator sides. The comparator side of the face fails
to show similar levels of relative moisture content. Thus, the objective
measurement and substantiation of the stratum corneum's electrical
conductivity shows a significant enhancement in facial skin moisture
content.

Example 13

[0080] A test of the ability of the Formulas A-F and H relative to the
comparators of Formulas G and I to reduce skin dryness is performed with
or without supplemental moisturizer. Twelve panelists who demonstrate
skin dryness upon repeated soap washing of the hands are selected to
participate in this study. Initially, the panelists induce a condition of
dryness by washing their hands with bar soap. The test formulations are
applied daily to one hand while the other is left untreated to serve as a
control side. Each hand is rated randomly by two trained evaluators who
have no knowledge of which hand is treated. The evaluators use a
stereomicroscope to assist them with their ratings. The results of this
study are expected to demonstrate that the unmoisturized comparator hand
shows additional dryness compared to the control hand. This level of
dryness is improved by application of moisturizer after each comparator
application. Formula A-F and H treated hands show marked improvement in
moisture content. The addition of moisturizer after each Formula A-F and
H application does not appreciably improve the treated skin moisture
content. The Formula A-F and H benefits should persist for twenty-four
hours after the final treatment indicating that the Formula A-F and H
compositions provide effective long-lasting moisturization.

[0082] Phase 2 is formed by combination of methyl perfluorobutyl ether
(and) methyl perfluoroisobutyl ether (CF-61) at 35% w/w final and the
remainder ethyl trisiloxane with continuous non-vortex propeller mixing
until a clear solution is formed.

[0083] Phase 2 is slowly combined with phase 1 with continuous non-vortex
propeller mixing. If a hazy solution is observed it will clarify upon
standing for 24-48 hours at ambient temperature.

[0087] Fifteen females aged 20 to 39 apply Formula J or K to one side of
their faces and the benzolyl peroxide comparator to the other side once
daily for two weeks. Each subject is asked to record any side effects
such as dryness, irritation, and perceived skin clarification. Both the
Formula J and K, as well as the comparator are expected to demonstrate
similar skin clarification. Subjects report less irritation and improved
skin condition on the Formula J or K treated side relative to comparator.

[0088] Various modifications of the present invention, in addition to
those shown and described herein, will be apparent to those skilled in
the art of the above description. Such modifications are also intended to
fall within the scope of the appended claims.

[0089] Patents and publications mentioned in the specification are
indicative of the levels of those skilled in the art to which the
invention pertains. These patents and publications are incorporated
herein by reference to the same extent as if each individual application
or publication was specifically and individually incorporated herein by
reference.

[0090] The foregoing description is illustrative of particular embodiments
of the invention, but is not meant to be a limitation upon the practice
thereof. The following claims, including all equivalents thereof, are
intended to define the scope of the invention.